The winner of the Royal Irish Academy/Irish Times biochemistry writing competition, Brona Murphy, describes how controlled cell death is the key to life
During the development of a child in the womb, vast numbers of cells areproduced from a single-cell embryo to produce the wonderful complexity of the human form. But have you ever wondered how the complex and intricate features of the face, of the hands, of the heart, are achieved?
The answer to this is not a simple one, as early development is still a fairly mysterious process. However, recent research suggests that organs are shaped by sculpting tissues into their final form through a process called programmed cell death or apoptosis.
During development, many more cells are produced than are actually needed and these extra cells die in a highly precise and regulated manner to allow the embryo to mature and develop correctly.
Even after birth our cells need to be renewed on a constant basis due to natural wear and tear and exposure to harmful agents in our environment. Every day we lose approximately 10 billion cells just to make room for new ones. In the 10 minutes it will take you to read this article seven million of your cells will have died.
Every day our bodies are bombarded with agents that damage the material that makes up our genes, our DNA. These agents of destruction include UV rays from the sun, cigarette smoke and chemicals in our food.
If the DNA is damaged beyond repair then these cells must be removed quickly and this is also achieved through apoptosis. But what exactly is apoptosis and how is it controlled?
The term apoptosis is derived from the Greek and means to drop or fall off, as leaves do from the trees in autumn. It was first used in modern scientific writing in 1972 by a group of scientists working in Edinburgh, to describe a very distinct mode of cell death.
During apoptosis, the cell shrinks and loses its shape as it undergoes dramatic internal reorganisation. Remarkably, the dying cell does not release any of its contents into its surroundings and becomes neatly packaged for disposal. Eventually the shrivelled cell is eaten by neighbouring cells and leaves no trace of its existence behind.
The analogy of a leaf falling from a tree is very apt in this context. As the leaf dies it shrivels and falls to the ground where it is absorbed into the soil to be used again. It dies alone, without disturbing any other leaves. Its death allows a new leaf to grow in its place. The cycle of life and death continues undisturbed.
In a similar way, controlled apoptosis is a very desirable form of cell death. However, uncontrolled apoptosis can have catastrophic effects. In cancer for example, cells typically lose their ability to die, resulting in uncontrolled cell growth and tumour development. In many brain disorders, like Alzheimer's and Parkinson's disease it is the other extreme. Here, too many cells die and the brain is damaged irrevocably.
It is now known that the destruction of a cell via apoptosis is a highly regulated process. Such tight control is not surprising when one considers that uncontrolled apoptosis can lead to conditions such as cancer and Alzheimer's disease
For the above reasons, deciphering the intricacies of how apoptosis is regulated will yield insights into the mechanisms underpinning these diseases and assist the search for effective treatments. Consequently, extensive research is currently being conducted in this particular area of the life sciences.
IT IS now known that the key players in apoptosis are enzymes called caspases. Caspases are proteins that can destroy other proteins within a cell. Twelve different "flavors" of caspase are present in our cells, seven of which play a direct role in apoptosis.
In a healthy cell the caspases are present but inactive. However, once a cell has received a signal to die, for example caused by damage to its DNA, the caspases become activated and proceed to dismantle the cell.
If one could imagine the process of apoptosis as a type of controlled demolition, then the active caspases play the role of the explosives. Unless their fuses are lit, these "explosives" are harmless, but once ignited they are deadly.
But how are these destructive enzymes activated? How do they orchestrate the dismantling of the cell during apoptosis?
Understanding the mode of action of the caspases is an exciting area of current research. In the Genetics Department at TCD, Prof Seamus Martin and his research team are gearing their efforts towards understanding exactly how caspases kill.
In general, caspases become activated in a domino effect. If one caspase becomes activated, this can lead to the activation of many others within the cell. As more and more caspases are activated the death signal is amplified. To use the analogy of explosives again, once one is lit, it can ignite others and collectively these can wreak controlled havoc.
Thus, the activation of the caspases is a central event in apoptosis as it represents the point of no return. For this reason much research is now focused on the regulation of caspase activation.
It is hoped that by understanding how apoptosis is "switched on" this will help in the treatment of many conditions where it would be desirable to kill cells, or conversely, keep them alive.
For example, a drug that could selectively switch on the caspases in tumour cells would represent a major breakthrough in cancer therapy. Similarly, a drug that could prevent apoptosis in brain cells would be of great benefit to individuals with Alzheimer's disease.
While such therapies are still unavailable, considerable progress is being made in understanding the intricacies of the cell death machinery. Due to the significant research effort of many labs worldwide it is now clear that cells die in a highly organised manner. Many of the players involved, such as caspases, are known. But there are undoubtedly many more that have yet to be discovered.
In fact, the more we discover about apoptosis the more certain we become of one thing - that the key to life may be cell death.
Brona Murphy is a third-year PhD student working in the Molecular Cell Biology Laboratory, Department of Genetics, Trinity College Dublin.